Process for preparing prostalglandin derivatives and stereospecific starting material thereof

ABSTRACT

The present invention relates to a process for effectively preparing prostaglandin derivatives and to a stereospecific alkyl halide containing 15S-alcohol group as a starting material.

TECHNICAL FIELD

[0001] The present invention relates to a novel process for preparing aprostaglandin derivative of the following formula (1):

[0002] in which

[0003] R₁ represents H or C₁-C₅-alkyl,

[0004] X represents CH₂, O, or S, and

[0005] R′ represents C₂-C₄-alkyl; phenyl optionally substituted byhalogen, C₁-C₅-alkyl, C₁-C₄-alkoxy, CF₃, or C₁-C₃-aliphatic acylamino;5- or 6-membered heterocycle containing one or more hetero atomsselected from a group consisting of nitrogen, oxygen and sulfur;C₃-C₇-cycloalkyl; or C₃-C₇-cycloalkenyl,

[0006] a 13,14-dihydro-PGF_(2n) ester derivative, and to an alkyl halideof the following formula (3a):

[0007] in which

[0008] Y′ represents Br or I, and

[0009] R″ represents a hydroxy-protecting group, preferablytrimethylsilyl, triethylsilyl, t-butyldimethylsilyl,t-butyldiphenylsilyl, phenyldimethylsilyl, or tetrahydrofuranyl, as astarting material.

BACKGROUIND ART

[0010] Prostaglandin derivative of the above formula (1) is known inDrugs of the Future, 1992, 17(8), 691-704; J. Med. Chem., 1993, 36,243-248, etc. and a process of the following Reaction Scheme 1 publishedin WO 93/00329 can be mentioned as the typical synthesis thereof.

[0011] In the above process, ω-chain is introduced into the startingmaterial of Corey lactone by Wadworth-Emmons method, the ketone group atC15 position is reduced to an alcohol group, the remained double bond isreduced again using Pd, α-chain is introduced into a lactol as obtainedthrough some consecutive reactions by Wittig reaction, and the terminalgroup is esterified.

[0012] However, the above process has been identified to have thefollowing problems.

[0013] First, the diastereomeric mixture resulted from the introductionof ω-chain and reduction of the ketone gorup at C15 position comprises15S-isomer and 15R-isomer in a ratio of 7:3. Therefore,stereoselectivity of the process is not satisfactory. Further, sincethese isomers can hardly be separated, the yield of the desired15S-isomer is as very low as 38%.

[0014] Second, the yield of the esterification reaction of the terminalcarboxylic acid after introduction of α-chain by Wittig reaction isreported to be less than 40%. This is the final step of the process, andso the low yield of the final step reaction may exert fatal and seriousinfluence on the total efficacy of the synthesis.

[0015] Third, Corey lactone used as a starting material is veryexpensive, which makes the total process uneconomic.

DISCLOSURE OF INVENTION

[0016] Thus, the present inventors have extensively studied to developan economic and effective process for preparing the compound of formula(1) by solving the problems of prior arts as explained above. As aresult, we newly designed an alkyl halide containing 15S-alcohol groupand then completed a process for preparing the compound of formula (1),starting from 1,4-addition reaction at the α,β-unsaturated ketone group.According to the process of the present invention, the yield may beincreased by using a stereospecific starting material instead ofreducing the C15 ketone in a poor stereoselective manner; particularly,the low efficacy due to the low yield of esterification reaction of theterminal carboxylic acid may be improved; and there is no more need touse the expensive Corey lactone as a starting material. Therefore, thepresent invention provides an economic and effective synthetic processthat is suitable for a mass production.

[0017] Therefore, an object of the present invention is to provide aprocess for preparing a prostaglandin derivative of formula (1).

[0018] It is another object of the present invention to provide an alkylhalide of formula (3a) as an effective starting material.

BEST MODE FOR CARRYING OUT THE INVENTION

[0019] The present invention relates to a process for preparing acompound of the following formula (1):

[0020] in which

[0021] R₁ represents H or C₁-C₅-alkyl,

[0022] X represents CH₂, O, or S, and

[0023] R′ represents C₂-C₄-alkyl; phenyl optionally substituted byhalogen, C₁-C₅-alkyl, C₁-C₄-alkoxy, CF₃, C₁-C₃-aliphatic acylamino; 5-or 6-membered heterocycle containing one or more hetero atoms selectedfrom a group consisting of nitrogen, oxygen and sulfur;C₃-C₇-cycloalkyl; or C₃-C₇-cycloalkenyl, which comprises the first stepwherein an alkyl halide containing 15S-alcohol of the following formula(3):

[0024] in which

[0025] X and R′ are defined as above,

[0026] Y represents a leaving group, preferably halogen, and

[0027] R″ represents a hydroxy-protecting group, preferablytrimethylsilyl, triethylsilyl, t-butyldimethylsilyl,t-butyldiphenylsilyl, phenyldimethylsilyl, or tetrahydrofuranyl, isconverted into a cuprate thereof and the cuprate compound is subjectedto a stereoselective 1,4-addition reaction to an α,β-unsaturated ketonecompound of the following formula (2):

[0028] in which

[0029] R₁ is defined as above, and

[0030] R₂ represents a hydroxy-protecting group, preferablytrimethylsilyl, triethylsilyl, t-butyldimethylsilyl,t-butyldiphenylsilyl, phenyldimethylsilyl, or tetrahydrofuranyl, to givea compound of the following formula (4):

[0031] in which X, R′, R″, R₁ and R₂ are defined as above; the secondstep wherein the ketone group on the cyclopentanone ring of the compoundof formula (4) is reduced using a metal hydride to give an α-alcoholcompound of the following formula (5):

[0032] in which X, R′, R″, R₁ and R₂ are defined as above; and the thirdstep wherein the alcohol protecting groups on the cyclopentanone ringand ω-chain in the compound of formula (5) are removed to give thecompound of formula (1).

[0033] The process according to the present invention is depicted in thefollowing Reaction Scheme 2 below.

[0034] The process of the present invention proceeds through threesteps, each of which is specifically explained in the following.

[0035] The First Step: Preparation of the Compound of Formula (4) fromthe Compounds of Formulae (2) and (3)

[0036] The cuprate compound that is formed from the alkyl halide offormula (3) by various methods as explained below is subjected to1,4-addition reaction to the α,β-unsaturated ketone group of thecompound of formula (2) to give the compound of formula (4). Here, thecuprate compound is introduced into the opposite side to the alkoxygroup on the cyclopentenone due to the steric hindrance of the alkoxygroup, resulting in a trans configuration with respect to the alkoxygroup. The ω-chain thus introduced causes another steric hindrance tothe α-chain of the cyclopentenone, whereby the compound of formula (4)in which α-chain and ω-chain have a trans configuration to each other isobtained.

[0037] The cuprate compound can be obtained from the compound of formula(3) by i) adding t-BuLi and then adding one substance selected from agroup consisting of CuCN, (2-thienyl)Cu(CN)Li and MeCu(CN)Li to thecompound of formula (3); or ii) adding one substance selected from agroup consisting of CuBr. DMS, CuI and CuBr to a Grignard reagent thatis formed from magnesium and the compound of formula (3).

[0038] Below, the process for preparing the compound of formula (4) fromthe alkyl halide of formula (3), where the cuprate compound acts as anintermediate, is specifically explained.

[0039] Method {circle over (a)}

[0040] To 2 equivalents of the compound of formula (3) dissolved in asolvent is added 4 equivalents of t-BuLi at −78° C., which is thenstirred. 1 equivalent of CuCN is added thereto. The temperature of thereaction solution is raised to −10° C. to give a lower order-cuprate ina homogeneous state. This cuprate is cooled again to −78° C. and thenreacted with 0.8-1.0 equivalent of the compound of formula (2).

[0041] Method {circle over (b)}

[0042] To 1 equivalent of the compound of formula (3) dissolved in asolvent is added 2 equivalents of t-BuLi at −78° C., which is thenstirred. 1 equivalent of (2-thienyl)Cu(CN)Li or MeCu(CN)Li is addedthereto. The temperature of the reaction solution is slowly raised to−40° C. over 30 minutes and then lowered again to −78° C. to give ahigher order-cuprate. This cuprate is reacted with 0.8-1.0 equivalent ofthe compound of formula (2).

[0043] Method {circle over (c)}

[0044] To 1 equivalent of the compound of formula (3) dissolved in asolvent is added 3-4 equivalents of Mg. The Grignard solution thusobtained is cooled to −78° C., and 0.3-1 equivalent of a substanceselected from a group consisting of CuBr. DMS, CuI, and CuBr is added.The reaction mixture is stirred for 1 hour to give Normant reagent. Thisreagent is reacted with 0.8-1.0 equivalent of the compound of formula(2).

[0045] The compound of formula (3) used as a starting material in theabove may be obtained by a process as exemplified in the followingReaction Scheme 3.

[0046] That is, a nucleophile, preferably carbanion, phenol, thiophenol,or alkaline salt of phenol or thiophenol, is reacted with a chiralepoxide that can be prepared by a process known in J. Chem. Research(S),1983, 10-11 to open the ring in a stereospecific manner to give analcohol compound having S stereochemistry. Particularly, in the case ofcarbanion, the alcohol compound can be obtained by adding 1˜2equivalents of a Grignard reagent and a catalytic amount (0.05˜0.5equivalent) of a substance selected from a group consisting of CuI,CuBr, and CuBr. DMS, stirring for 10 minutes, and slowly adding dropwisean epoxide in a solvent selected from a group consisting ofdiethylether, tetrahydrofuran and dimethylsulfide at reactiontemperatures of −20˜20° C.

[0047] Then, the alcohol is protected by a hydroxy-protecting group,preferably triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl,phenyldimethylsilyl, or tetrahydrofuranyl, and the protecting group ofthe primary alcohol is removed. Particularly, the benzyl group used as aprotecting group can be removed by a catalytic hydrogenation reaction ina solvent selected from a group consisting of methanol and ethanol, andin the presence of palladium as a catalyst; and the paramethoxybenzylgroup can be removed in a solvent mixture of dichloromethane and waterin the presence of DDQ(2,3-dichloro-5,6-dicyano-1,4-benzoquinone)(1.0˜2.0 equivalent) at roomtemperature.

[0048] Finally, the primary alcohol is iodinated by I₂, PPh₃, andimidazole in a solvent mixture of acetonitrile and diethylether; orbrominated by CBr₄ and PPh₃, or reacting with methane sulfonyl chlorideand triethylamine to give a methanesulfonate, which is then reacted withLiBr in THF solvent.

[0049] Particularly, a compound of the following formula (3a) among thecompound of formula (3):

[0050] in which Y′ represents Br or I, and R″ represents ahydroxy-protecting group, is novel, and thus, it is another object ofthe present invention to provide the novel compound of formula (3a).

[0051] The compound of formula (2) can be prepared according to aprocess described in J. Org. Chem., 1978, 43, 1641-1643, and(2-thienyl)Cu(CN)Li or MeCu(CN)Li can be obtained by adding thecommercially available 2-thienyl lithium or MeLi to CuCN.

[0052] In the above reaction, the solvent dissolving the compounds offormulae (2) and (3) is selected from a group consisting oftetrahydrofuran and diethylether, and the solvent dissolving t-BuLi isn-pentane. After the completion of each reaction, an aqueous solution ofNH₄Cl/NH₄OH (9/1) is added to stop the reaction, Then, the reactionsolution is extracted with diethylether, concentrated, and purified bycolumn chromatography.

[0053] The Second Step: Preparation of the Compound of Formula (5) byReduction of the Compound of Formula (4)

[0054] The compound of formula (4) obtained by the above 1,4-additionreaction has a ketone group, which can be reduced by various metalhydrides. As the metal hydrides that can be used, those having a heavysteric hindrance, preferably those selected from a group consisting ofsodiumborohydride (NaBH₄), L-selectride, N-selectride and K-selectride,and particularly preferably L-selectride can be mentioned. This isbecause the hydride is apt to attack the cyclopentanone ring from theopposite direction with respect to the alkoxy group in the compound offormula (4) due to the steric hindrance of the alkoxy group, as themetal hydride is bulkier, to selectively give the desired α-alcohol. Thereaction is carried out by adding 1˜3 equivalents of L-selectride to 1equivalent of the compound of formula (4) dissolved in a solvent at −78°C., stirring for 1 to 2 hours, and adding 30% H₂O₂ to stop the reaction.The reaction solution is stirred for 30 minutes at 0° C., extracted withdiethylether, and concentrated to give the compound of formula (5) in astereoselective manner. This compound is used in the next reactionwithout further purification. The solvent used in the above reaction isselected from a group consisting of tetrahydrofuran, diethylether anddichloromethane.

[0055] The Third Step: Preparation of the Compound of Formula (1)through Deprotection of the Compound of Formula (5)

[0056] The two alcohol protecting groups in the compound of formula (5)can be removed under an acidic condition, or by using various fluorides(F) particularly when the protecting group is silyl. More specifically,the following methods can be exemplified.

[0057] Method using an Acidic Condition

[0058] Method {circle over (a)}

[0059] Deprotection is achieved by stirring for 24˜48 hours at roomtemperature in the presence of excess NaHSO₄ in a solvent mixture oftetrahydrofuran and water (2:1).

[0060] Method using Fluorides

[0061] Deprotection is achieved by

[0062] stirring for 4 hours at 0° C.˜room temperature in the presence of2˜4 equivalents of tetrabutylammonium fluoride (Bu₄N⁺F⁻) in a solvent oftetrahydrofuran (Method {circle over (b)}; or

[0063] reacting for 3˜4 hours at 0° C. with 2˜10 equivalents of hydrogenfluoride pyridine (HF-pyridine) in a solvent of dichloromethane (Method{circle over (c)}; or

[0064] reacting for 4 hours with fluorosilicic acid (H₂SiF₆) in asolvent of acetonitrile according to DeShong method (J. Org. Chem.,1992, 57, 2492) (Method {circle over (d)}).

[0065] The present invention will be more specifically explained in thefollowing examples. However, it should be understood that the followingexamples are intended to illustrate the present invention but not in anymanner to limit the scope of the present invention.

EXAMPLE 1 Preparation of the Compound of Formula (3)

[0066] Preparation of 1-(4-methoxy-benzyloxy)-5-phenyl-pentan-3-ol

[0067] Benzyl magnesium chloride (2.0M in TBF) (64.6 ml, 129.2 mmol) wasadded to Th (77 ml) and cooled to 0° C. CuI (1.9 g, 9.94 mmol) wasadded, and the mixture was stirred for 10 minutes.2-[2-(4-Methoxy-benzyloxy)-ethyl]-oxirane (19.5 g, 99.4 mmol) dissolvedin THF (120 ml) was slowly added dropwise thereto. The reaction mixturewas stirred for 1 hour at room temperature and saturated aqueous NH₄Clsolution (100 ml) was added to separate the organic layer. The aqueouslayer was extracted with diethylether (100 ml×2). The organic layerswere combined, washed with saturated aqueous NaCl solution, dried overMgSO₄, filtered, and concentrated to give1-(4-methoxy-benzyloxy)-5-phenyl-pentan-(S)-3-ol (30 g) of a pale yellowoil. This compound was used in the next reaction without furtherpurification.

[0068] Preparation of(S)-3-(t-butyldimethylsilyloxy)-5-(4-methoxy-benzyloxy)-1-phenyl Pentane

[0069] To DMF (390 ml) were added1-(4-methoxy-benzyloxy)-5-phenyl-pentan-(S)-3-ol (30 g unpurified),imidazole (20.3 g, 298.2 mmol) and TBDMSCI (23 g, 149.8 mmol) in theorder, and the resulting mixture was stirred for 12 hours at roomtemperature. After completion of reaction, the reaction mixture wasdiluted with water (500 ml) and extracted with ethyl acetate (100 ml×3).The organic layers were combined, washed with saturated aqueous NaClsolution, dried over MgSO₄, filtered, and concentrated. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=20:1)to give (S)-3-(t-butyldimethylsilyloxy)-5-(4-methoxy-benzyloxy)-1-phenylpentane (35 g, Yield of 2 steps 85%) of a colorless and transparent oil.

[0070] Preparation of(S)-3-(t-butyldimethylsilyloxy)-5-phenyl-pentan-1-ol

[0071] (S)-3-(t-butyl dimethylsilyloxy)-5-(4-methoxy-benzyloxy)-1-phenylpentane (15 g, 36.2 mmol) was dissolved in a solvent mixture ofdichloromethane-water (20:1) (252 ml). DDQ (8.2 g, 36.2 mmol) was addedthereto and the mixture was stirred for 30 minutes at room temperature.After completion of the reaction, saturated aqueous NaHCO₃ solution (100ml) was added to the reaction solution to stop the reaction. The organiclayer was separated and the aqueous layer was extracted withdichloromethane. The organic layers were combined, washed with saturatedaqueous NaHCO₃ solution and saturated aqueous NaCl solution, dried overMgSO₄, filtered, and concentrated. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=15:1) to give(S)-3-(t-butyldimethylsilyloxy)-5-phenyl-pentan-1-ol (10.6 g, Yield 99%)of a yellow oil.

[0072] Preparation of (S)-3-(t-butyldimethylsilyloxy)-5-bromo-1-phenylpentane

[0073] (S)-3-(t-butyldimethylsilyloxy)-5-phenyl-pentan-1-ol (10.6 g, 36mmol) was dissolved in dichloromethane (80 ml), triethylamine (12.6 ml,90.5 mmol) was added, and the mixture was cooled to 0° C. Methanesulfonyl chloride (4.2 ml, 54.3 mmol) was slowly added dropwise and theresulting mixture was stirred for 12 hours. After completion of thereaction, the reaction mixture was diluted with water (50 ml). Theorganic layer was separated and the aqueous layer was extracted withdichloromethane (50 ml×2). The organic layers were combined, washed withsaturated aqueous NaCl solution, dried over MgSO₄, filtered, andconcentrated. Without further purification, the residue was dissolved inTHF (60 ml). LiBr (7.86 g, 90.5 mmol) was added thereto and the mixturewas refluxed for 4 hours. After completion of the reaction, water (80ml) was added to the reaction solution which was then extracted withdiethylether. The organic layers were combined, washed with saturatedaqueous NaCl solution, dried over MgSO₄, filtered, and concentrated. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=20:1) to give colorless and transparent(S)-3-(t-butyldimethylsilyloxy)-5-bromo-1-phenyl pentane (11 g. Yield86%).

EXAMPLE 2 Preparation of the Compound of Formula (4) According to Method{circle over (a)}

[0074] (S)-3-(t-butyldimethylsilyloxy)-5-bromo-1-phenyl pentane (8 mmol)was dissolved in diethylether (17 ml) and cooled to −78° C. t-BuLi(1.7Mpentane solution, 16 mmol) was slowly added dropwise thereto and themixture was stirred for 20 minutes. Then, CuCN (4 mmol) was added andthe temperature of the reaction solution was slowly raised to −10° C. tomake the solution homogeneous. The reaction solution was cooled again to−78° C.7-[(R)-3-(t-butyldimethylsilyloxy)-5-oxo-cyclopent-1-enyl]-hept-5-enoicacid isopropyl ester (3.25 mmol) dissolved in Et₂O (2.5 ml) was slowlyadded dropwise and the mixture was stirred for 2 hours. The temperatureof the reaction solution was raised to −30° C., the reaction was stoppedby the addition of 20 ml of saturated aqueous NH₄Cl solution/28% aqueousNH₄OH solution (9/1), and the reaction solution was warmed to roomtemperature. The reaction solution was diluted with diethylether, washedwith water and brine, dried over Na₂SO₄, filtered, and concentratedunder vacuum. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=20:1) to give11,15-O-bis(t-butyldimethylsilyl)-13,14-dihydro-17-phenyl PGE_(2α)isopropyl ester in a yield of 82%.

EXAMPLE 3 Preparation of the Compound of Formula (4) According to Method{circle over (b)}

[0075] (S)-3-(t-butyldimethylsilyloxy)-5-bromo-1-phenyl pentane (3.5mmol) was dissolved in diethylether (30 ml) and cooled to −78° C. t-BuLi(1.7M pentane solution, 7.35 mmol) was added dropwise and the mixturewas stirred for 10 minutes. (2-Thienyl)Cu(CN)Li (0.25M TBF solution, 3mmol) which was newly prepared in another flask was added dropwisethereto. The reaction solution was slowly warmed to 40° C. over 30minutes and then cooled to −78° C. 7-[(R)-3-(t-butyldimethylsilyloxy)-5-oxo-cyclopent-1-enyl]-hept-5-enoic acid isopropyl ester (2.7mmol) dissolved in diethylether (15 ml) was slowly added dropwisethereto. Immediately after the dropwise addition, the reaction vesselwas transferred to a cryostat of −45° C., and then the reaction solutionwas warmed to −30° C. over 30 minutes. After completion of the reaction,the reaction was stopped by adding 10 ml of aqueous NH₄Cl/NH₄OH (9/1)solution. The reaction solution was warmed to room temperature, dilutedwith diethylether, washed with water and brine, dried over Na₂SO₄,filtered, and concentrated under vacuum. The residue was purified bysilica gel column chromatography (hexane:ethyl acetate=20:1) to give11,15-O-bis(t-butyldimethylsilyl)-13,14-dihydro-17-phenyl PGE_(2α)isopropyl ester in a yield of 83%.

EXAMPLE 4 Preparation of the Compound of Formula (4) According to Method{circle over (c)}

[0076] To a flask containing magnesium turning (25 mmol) was introduceda solution wherein (S)-3-(t-butyldimethylsilyloxy)-5-bromo-1-phenylpentane (8.3 mmol) and 1,2-dibromoethane (0.05 ml) were dissolved in THF(1.6 ml). The reaction solution was warmed in a thermostat of 70° C. toinitiate formation of Grignard reagent, cooled again to roomtemperature, and stirred for 30 minutes. This solution was diluted withTBF (5 ml), stirred for further 1.25 hour, and cooled to −78° C. CuBr(DMS) (2.0 mmol) dissolved in dimethylsulfide (4 ml) was added dropwiseand the mixture was stirred for 1 hour.7-[(R)-3-(t-butyldimethylsilyloxy)-5-oxo-cyclopent-1-enyl]-hept-5-enoicacid isopropyl ester (6.8 mmol) dissolved in diethylether (7 ml) wasslowly added dropwise thereto and the mixture was stirred for 1 hour.After completion of the reaction, the reaction solution was warmed to−30° C. The reaction was stopped by the addition of 20 ml of aqueousNH₄Cl/NH₄OH (9/1) solution, which was then warmed to room temperature.The reaction solution was diluted with diethylether, washed with waterand brine, dried over Na₂SO₄, filtered, and concentrated under vacuum.The residue was purified by silica gel column chromatography(hexane:ethyl acetate=20:1) to give11,15-O-bis(t-butyldimethylsilyl)-13,14-dihydro-17-phenyl PGE_(2α)isopropyl ester in a yield of 77%.

EXAMPLE 5 Preparation of the Compound of Formula (5)

[0077] 11,15-O-bis(t-butyldimethylsilyl)-13,14-dihydro-17-phenylPGE_(2α) isopropyl ester (3.67 mmol) was dissolved in THF (40 ml), thereaction solution was cooled to −78° C., and L-selectride (1M THFsolution, 7.35 mmol) was slowly added dropwise thereto. At thistemperature the reaction solution was stirred for 2 hours and thereaction was stopped by the addition of hydrogen peroxide (30% aqueoussolution, 16 mmol). The reaction solution was stirred for 30 minutes at0° C. and extracted with diethylether. The organic layers were combined,washed with water and brine, dried over magnesium sulfate, filtered, andconcentrated under vacuum. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=10:1) to give11,15-O-bis(t-butyldimethylsilyl)-13,14-dihydro-17-phenyl PGF_(2α)isopropyl ester in the yield of 90%.

EXAMPLE 6 Preparation of the Compound of Formula (1) According to Method{circle over (a)}

[0078] 11,15-O-bis(t-butyldimethylsilyl)-13,14-dihydro-17-phenylPGF_(2α) isopropyl ester (40.32 mmol) was dissolved in THF (25 ml),NaHSO₄.H₂O (17.3 mmol) dissolved in water (12.5 ml) was added thereto,and the mixture was stirred for 24 hours at room temperature. Aftercompletion of the reaction, the reaction solution was extracted withwater (20 ml) and CH₂Cl₂ (85 ml). The organic layers were combined,washed with saturated aqueous NaHCO₃ solution, dried over magnesiumsulfate, filtered, and concentrated. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=1:3) to give13,14-dihydro-17-phenyl PGF_(2α) isopropyl ester in a yield of 75%.

EXAMPLE 7 Preparation of the Compound of Formula (1) According to Method{circle over (c)}

[0079] 11,15-O-bis(t-butyldimethylsilyl)-13,14-dihydro-17-phenylPGF_(2α) isopropyl ester (1.22 mmol) was dissolved in dichloromethane(25 ml), HF.pyr (2.5 ml) was added thereto at 0° C., and the mixture wasstirred for 3 hours. After completion of the reaction, the reactionsolution was diluted with dichloromethane (10 ml), which was then pouredinto saturated aqueous NaHCO₃ solution of 0° C. The organic layer wasseparated and the aqueous layer was extracted with dichloromethane. Theorganic layers were combined, dried over magnesium sulfate, filtered,and concentrated. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=1:3) to give13,14-dihydro-17-phenyl PGF_(2α) isopropyl ester in the yield of 82%.

EXAMPLE 8 Preparation of the Compound of Formula (1) According to Method{circle over (d)}

[0080] 11,15-O-bis(t-butyldimethylsilyl)-13,14-dihydro-17-phenylPGF_(2α) isopropyl ester (3.6 mmol) was dissolved in acetonitrile (15ml), H₂SiF₆ (4 ml, 25% wt aqueous solution) was added dropwise theretoin an ice bath, and the mixture was warmed to room temperature andstirred for 4 hours. After completion of the reaction, saturated aqueousNaHCO₃ solution was added thereto. The aqueous layer was extracted withdichloromethane. The organic layers were combined, washed with water andbrine, dried over magnesium sulfate, filtered, and concentrated. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=1:3) to give 13,14-dihydro-17-phenyl PGF_(2α) isopropyl ester inthe yield of 95%.

INDUSTRLAL APPLICABILITY

[0081] In the process of the present invention, a stereospecificstarting material is used instead of reducing the ω-chain that maygenerate undesirable isomers and result in a yield decrease. Further,esterification of the carboxylic acid in the unstable prostaglandincompound in the final step can be avoided, which in turn results in ayield increase in a considerable degree. That is, the total yield of theprocess according to the present invention is 38 to 51% based on theyields of examples above, which is much higher than the maximum yield of15% of the previous process. Moreover, according to the presentinvention, the 15R-isomer resulted from the reduction of ω-chain as animpurity, which can hardly be removed, is not generated, and also theproduction of impurity from the esterification reaction can beprevented. As a result, the prostaglandin derivative of formula (1) canbe easily purified, and so can be synthesized in an economic andeffective manner.

1. A process for preparing a compound of the following formula (1):

in which R₁ represents H or C₁-C₅-alkyl, X represents CH₂, O, or S, andR′ represents C₂-C₄-alkyl; phenyl optionally substituted by halogen,C₁-C₅-alkyl, C₁-C₄-alkoxy, CF₃, C₁-C₃-aliphatic acylamino; 5- or6-membered heterocycle containing one or more hetero atoms selected froma group consisting of nitrogen, oxygen and sulfur; C₃-C₇-cycloalkyl; orC₃-C₇-cycloalkenyl, which comprises the first step wherein an alkylhalide containing 15S-alcohol of the following formula (3):

in which X and R′ are defined as above, Y represents a leaving group,and R″ represents a hydroxy-protecting group, is converted into acuprate thereof and the cuprate compound is subjected to astereoselective 1,4-addition reaction to an α,β-unsaturated ketonecompound of the following formula (2):

in which R₁ is defined as above, and R₂ represents a hydroxy-protectinggroup, to give a compound of the following formula (4):

in which X, R′, R″, R₁ and R₂ are defined as above; the second stepwherein the ketone group on the cyclopentanone ring of the compound offormula (4) is reduced using a metal hydride to give an α-alcoholcompound of the following formula (5):

in which X, R′, R″, R₁ and R₂ are defined as above; and the third stepwherein the alcohol protecting groups on the cyclopentanone ring andω-chain in the compound of formula (5) are removed to give the compoundof formula (1).
 2. The process of claim 1 wherein the compound offormula (3) is converted into its cuprate by i) adding t-BuLi and thenadding one substance selected from a group consisting of CuCN,(2-thienyl)Cu(CN)Li and MeCu(CN)Li to the compound of formula (3); orii) adding one substance selected from a group consisting of CuBr DMS,CuI and CuBr to a Grignard reagent which is formed from magnesium andthe compound of formula (3).
 3. The process of claim 1 wherein the metalhydride is selected from a group consisting of sodiumborohydride NaBH₄),L-selectride, N-selectride and K-selectride.
 4. The process of claim 1wherein the alcohol protecting groups are removed in the presence of H⁺or F⁻.
 5. A compound of the following formula (3a):

in which Y′ represents Br or I, and R″ represents a hydroxy-protectinggroup.